Acylnitrene route to vicinal amino alcohols. Application to the synthesis of (-)-bestatin and analogues

Bestatin, valinoctin A, and microginin are naturally occurring small peptides containing a nonproteinogenic alpha-hydroxy-beta-amino acid at the N-terminus of the peptide chain. We report here our development of a general method for the synthesis of alpha-hydroxy-beta-amino acids and exemplify this with a synthesis of (-)-bestatin and analogues. Our synthesis utilizes an intramolecular acylnitrene-mediated aziridination to generate a key bicyclic aziridine in excellent yield and stereoselectivity. This bicyclic aziridine can be opened with a number of organometallic reagents to provide a series of substituted oxazolidinones. The oxazolidinones are readily converted to bestatin and a series of bestatin analogues. As part of this approach, we have developed a new method for the synthesis of azidoformates. We have also demonstrated that oxazolidinones can be selectively hydrolyzed in the presence of peptide bonds. This acylnitrene route to bestatin should prove useful for the synthesis of a variety of analogues of bestatin as well as other alpha-hydroxy-beta-amino acids and their corresponding peptides.